Some micro-organisms such as Streptococci, Salmonella, E.coli and S.aureus may cause severe invasive infections such as sepsis or septic shock. Fever, hypotension and bleeding disorders are common symptoms of sepsis and septic shock. Invasive infections caused by these bacteria may result from resistance to antibiotics or defects in the immune system of the infected individual.
The endogenous or intrinsic pathway of inflammation and coagulation is triggered by assembly of the contact phases system. The contact phase system is orchestrated by three serine proteases, factor XI (hereinafter referred to as F XI), factor XII (F XII) and plasma kallikrein (PK) as well as the non-enzymatic co-factor H-kininogen (HK). H-kininogen forms equimolar complexes with F XI and PK. The local activation of this proteolytic system triggers different cascades such as the surface-dependent activation of blood coagulation, fibrinolysis, kinin generation and inflammation reactions.
Events which allow the assembly of the contact phase components lead to conversion of F XII to the active enzyme F XIIa which triggers the contact phase system. Partially activated V XII cleaves PK which is bound to surfaces via HK. By a mechanism of reciprocal activation, PK amplifies the activity of F XII and in addition PK cleaves HK to release the nona peptide bradykinin. Activated F XII cleaves F XI into its active form which leads to initiation of the intrinsic pathway of coagulation.
Bradykinin and the physiologically important related peptides kallidin (Lys-bradykinin) and Met-Lys bradykinin, contract smooth muscle for example to produce diarrheoa and inflammatory bowel disease and asthma, lower blood pressure, mediate inflammation as in allergies, arthritis and asthma, participate in blood clotting and complement-mediated reaction in the body, mediate rhinitis (viral, allergic and non-allergic) and are over produced in pathological conditions such as acute pancreatitis, hereditary angioneurotic edema, post-gastrectomy dumping syndrome, carcinoid syndrome, anaphylactic shock, reduced sperm mobility and certain other conditions.
As a result of the fact that bradykinin is involved in all the above mentioned clinical indications, a large number of bradykinin antagonists have been developed. Such antagonists are disclosed in e.g. U.S. Pat. No. 4,693,993. Wirth et al., Can. J. Physiol. Pharmacol. Vol. 73 pp 797-804 presents clinical studies regarding administering bradykinin antagonists for treating post-operative pain, asthma, anaphylactoid reactions, systemic inflammatory response syndrome, and suspected sepsis, head injury and hantavirus infections. A review on clinical applications of bradykinin antagonists can be found in Cheronis et al. eds: Proteases, Protease Inhibitors and Protease Derived Peptides pp 167-176. Although these citations disclose administration of bradykinin antagonists for treating sepsis, it is evident that the suspected sepsis treated by said antagonists it not primarily caused by bacterial infections. Accordingly the citations are completely silent about using bradykinin antagonists for treating bacterial infections. Moreover it is evident that bradykinin antagonists have been administered to relieve the symptoms of inflammation.